The study examined the effect of low-dose epidural esketamine (0.5 mg/kg) combined with labor analgesia on postpartum depressive symptoms in 299 women after spontaneous labor. The women were divided into three groups: group A (esketamine + analgesia), group B (analgesia alone) and group C (analgesia alone). The primary measure was the Edinburgh Postnatal Depression Scale (EPDS) score at 42 days postpartum. At forty-two days postpartum, there was no statistically significant difference in EPDS scores between group A (1.97 ± 1.74) and group B (2.01 ± 1.68), with a mean difference of -0.03 (95% CI: -0.46 to 0.39, p = 0.88). The incidence of screen-positive depression (EPDS ≥10) was comparable: 4% in group A, 2% in group B, and 6% in group C. In all groups, there was a temporary improvement in depressive symptoms and pain, associated with a decrease in estrogen and an increase in cortisol after delivery. In the low-risk group with low baseline symptoms, esketamine did not significantly reduce EPDS scores compared to analgesia alone. The study recommends further research in high-risk populations.